tbuckley/cabot-search huggingface dataset:
Abstract 2708: Nano-immunotherapy: efficacy of nanoconjugate QN-247 in a triple negative breast cancer (TNBC) mouse model
Authors: Tariq Arshad, Stephen Fait, Guy Gammon, Andrew Hertig, Mark J. Sarno
Journal: Cancer Research (2023)

Abstract Introduction and Purpose: Triple-negative breast cancer (TNBC) accounts for 12% of breast cancers (BC) in the US and 15% worldwide. It lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Compared to other types of BC, it is more aggressive and has higher risks of recurrence. In the metastatic setting, survival outcomes are much worse than other BC subtypes, with a 5-years survival rate of 8-16%. There is an urgent need to develop better treatment options for TNBC patients. We have developed a novel therapeutic, QN-247, by conjugating an anti-proliferative DNA aptamer to gold nanospheres. The aptamer-gold nanosphere construct shows increased half-life and cytotoxic effects relative to the aptamer alone. QN-247 inhibits nucleolin, a key regulatory protein overexpressed in triple-negative breast cancer (TNBC) cells, thereby reducing their proliferation. Description of Experimental Procedures: A subcutaneous, TNBC model (MDA-MB-231 xenograft) in nude mice was used in this efficacy study. When tumor volumes reached sufficient size (85 mm3), QN-247 test compound, aptamer alone, and vehicle control was administered daily (QD) at 1 mg/kg via intraperitoneal injection for 12 days. Tumor volumes and body weights were measured regularly through day 20. Nine animals were included in each treatment group. Summary of DataA statistically significant reduction in mean tumor volumes of QN-247 treated mice compared to the vehicle control and aptamer alone was observed. Tolerability of the QN-247 treatment was excellent with no evidence of toxicity. Statement of Conclusions: This study demonstrates that QN-247 exerts a powerful anti-tumor effect. Additional preclinical mouse xenograft tumor models will be treated with QN-247 to study its effect on other cancers. Citation Format: Tariq Arshad, Stephen Fait, Guy Gammon, Andrew Hertig, Mark J. Sarno. Nano-immunotherapy: efficacy of nanoconjugate QN-247 in a triple negative breast cancer (TNBC) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2708.
Abstract 188: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development
Authors: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj
Journal: Cancer Research (2023)

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, built on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with simultaneously expanded paired tumor infiltrating lymphocytes (TIL) as a source of tumor reactive cells. Our system allows robust expansion of TIL with preserved T-cell receptor repertoires and has an establishment rate of 75%. Paired resources allow for screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and allo-reactivity. For this purpose, we developed a organoid-TIL co-culture system which quantifies and characterizes tumor organoid apoptosis by combining image-based analysis with flow cytometry and cytokine release assays as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids. Our system offers a powerful tool for the development and validation of cancer immunotherapy and may help to stratify cancer patients for susceptibility of various types of immunotherapies. Citation Format: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 188.
Abstract 86: Chemotherapy-induced microenvironmental changes promote dormant breast cancer cell outgrowth in adipose tissue
Authors: Qihao Ren, Jiayu Ye, Xiaoyu Yuan, Sheila Stewart
Journal: Cancer Research (2023)

Abstract Despite the high 5-year survival rate for early-stage breast cancer patients, late recurrence of the disease remains a major challenge. Breast cancer can recur in approximately 20-25% of patients months to decades after an initial diagnosis, and there are few biomarkers that predict which patients will suffer from the recurrent disease. Unfortunately, this means clinicians and their patients must take a frustrating wait-and-see approach. Notably, disseminated tumor cells (DTCs) are frequently detected in early-stage breast cancer patients, and their presence predicts a higher chance of recurrence. However, why some patients with DTCs recur while others do not remains a mystery. Previous work has suggested that changes in the tumor microenvironment (TME) play an important role in the maintenance of tumor cell dormancy. When assessing the impact of doxorubicin (DOXO), a chemotherapeutic agent often used to treat breast cancer patients, on the TME, we noted that DOXO treatment led to the activation of dormant breast cancer cells in the visceral adipose tissue. Moreover, in accordance with the clinical observation that obese patients suffer a higher risk of cancer recurrence, we found that diet-induced obesity further exacerbated DOXO ability to reactivate dormant breast cancer cells in adipose tissue and this reactivation was associated with robust macrophage infiltration. These findings were interesting in light of our observation that tumor cells can metastasize to visceral fat depots in breast cancer patients. To understand why macrophages were recruited to the adipose tissue and how they led to tumor cell reactivation, we profiled the microenvironmental changes in visceral fat from Veh- and Doxo- treated mice using single-cell RNA-sequencing and found that the infiltrating macrophages exhibited unique pro-inflammatory and lipid-regulatory phenotypes. Our study provides novel insights into how TME impacts breast cancer dormancy and also highlights the importance of adipose tissue as a unique reservoir that potentiates cancer relapse. Citation Format: Qihao Ren, Jiayu Ye, Xiaoyu Yuan, Sheila Stewart. Chemotherapy-induced microenvironmental changes promote dormant breast cancer cell outgrowth in adipose tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 86.
Abstract 5901: Microbiome and genomic profiling in rectal adenocarcinoma
Authors: David Hein, Laura Coughlin, Nicole Poulides, Andrew Koh, Nina Sanford
Journal: Cancer Research (2023)

Abstract Introduction: Recent studies have identified bacteria associated with colorectal cancer (CRC), with some data supporting causality in preclinical CRC models. We examined the gut microbiome composition and tumor genomic profiles in a diverse cohort of rectal cancer patients. Methods: Twenty-two patients with newly-diagnosed, Stage II-IV rectal cancer without pathogenic germline mutations (mismatch repair genes, MUTYH) were included in the study. Gut microbiome profiling was performed on genomic DNA extracted from collected fecal samples (16S rRNA sequencing, V4 region). Tumor specimens were tested for somatic and germline mutations using the Tempus xT 648-gene panel and whole transcriptome RNA sequencing, providing information on tumor mutation burden (TMB), pathogenic KRAS mutation status and consensus molecular subtype (CMS). We then assessed differential abundance of microbial taxa (using ANCOM-BC) between the following groups: high vs low TMB (dichotomized at median, 3.7 mut/MB), presence versus absence of pathogenic KRAS mutation, and CMS subtype. Results: The median age of study subjects was 49 years (range 37-78). Racial/ethnic breakdown was as follows: 2 non-Hispanic Asian, 4 non-Hispanic Black, 5 non-Hispanic White, and 11 White Hispanic. Twelve tumors carried a pathogenic KRAS variant and the median TMB was 3.7 m/MB (range 0.5-8.9 m/MB). Among 20 tumors that underwent whole transcriptome RNA sequencing, 1 was categorized as CMS1, 8 CMS2, 3 CMS3, 7 CMS4, and 2 CMS undetermined. There were no statistically significant differences in gut bacteria taxa abundance by KRAS mutation status or among CMS subtypes. The group with greater than median TMB, however, had statistically significant enrichment of Pepostreptococcus stomatis (18.4 fold increase, p=0.039 after Benjamini-Hotchberg adjustment with FDR = 0.05). Conclusions: In this pilot study, we found that CRC patients with higher TMB had an enrichment of Peptostreptococcus stomatis, a bacteria associated with colonic dysplasia in mouse models and enriched in CRC patients as compared to healthy controls. (PMID 28823860, 35292756) Higher TMB is a predictive biomarker for response to immunotherapy across cancer types including CRC. Since the gut microbiome is potentially modifiable, further research is needed to better elucidate the connection between microbiome and CRC carcinogenesis including specific mutation profiles, which could pave the way for microbiome-related risk reduction or therapeutic strategies in CRC. Citation Format: David Hein, Laura Coughlin, Nicole Poulides, Andrew Koh, Nina Sanford. Microbiome and genomic profiling in rectal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5901.
Abstract 6043: Manipulation of mitochondrial metabolism, through SIRT3 agonists, in a novel immunoreactive melanoma organoids model
Authors: Azza M. El-derby, Nadeem Wajih, Jack Arbiser, Konstantinous Votanopoulos, Shay Soker
Journal: Cancer Research (2023)

Abstract The interplay between tumor cell metabolism and immune cells in the tumor microenvironment has emerged as a determinant factor in cancer progression and treatment. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that modulates ROS levels and governs many enzymes that regulate mitochondrial metabolism and homeostasis. SIRT3 has a dual role in cancer; it is regarded as an oncogene and tumor suppressor gene simultaneously. It has tumor-promoting action via keeping ROS levels low and favoring cell proliferation; on the contrary, it can trigger cell death under stress conditions by modulating tumor cell glycolysis. Recent data suggest a role for SIRT3 in cancer immunology with PD-L1 levels are found to be inversely associated with SIRT3 level in cervical cancer, and CD8+ T cells from SIRT3 knockout donor mice exhibited low GVHD in recipients. In this study, we explored the potential role of SIRT3 agonists in sensitizing the immunoreactivity of melanoma cells in a novel immunoreactive melanoma organoids model. We used the B16-F10 melanoma cell line spheroids to determine the effects of SIRT3 agonists on cellular viability, using an ATP assay. Validation of SIRT3 expression was determined via Western blot. Non-toxic amounts of SIRT3 agonists were also applied to melanoma organoids prepared from patient-derived metastatic melanoma from a lymph node. Preliminary results revealed a significant decrease in the viability of the organoids treated with R-propranolol (20µM) and Imipramine blue (0.25µM) agonists. We further investigated the effect of SIRT3 agonists R-propranolol and Imipramine blue on immunotherapy targeting PD-1, Pembrolizumab (100 nM) and Nivolumab (100 nM), and CTLA-4 inhibitor Ipilimumab (100 nM). We found a limited effect of Pembrolizumab and Nivolumab. Anti-tumor cytotoxicity was markedly increased in combination of Imipramine blue with Pembrolizumab and R-propranolol with Nivolumab. We propose that these effects are mediated through the activation of the endogenous immune cells and/or via the regulation of the PD-L1 and NKD2 ligand expression levels in the melanoma cells to become more sensitized to immune cells. Further studies will aim to validate these results in immunoreactive organoids from both mice and human patients. Our studies will shed light on the immune and metabolic axes and the use of specific agonists to develop new immune therapy treatment strategies for melanoma. Citation Format: Azza M. El-derby, Nadeem Wajih, Jack Arbiser, Konstantinous Votanopoulos, Shay Soker. Manipulation of mitochondrial metabolism, through SIRT3 agonists, in a novel immunoreactive melanoma organoids model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6043.
Abstract 6045: Role of PP2A methylation on methionine dependence of cancer
Authors: Anna Andronicos, Da-Wei Lin, Yi-Chen Su, Mari Ishak Gabra, Mei Kong, Peter Kaiser
Journal: Cancer Research (2023)

Abstract Dependence on exogenous methionine is a well-known, but poorly understood cancer-specific metabolic requirement. Although most cancer cells can convert homocysteine to methionine, they are unable to grow when methionine depleted media is supplemented with homocysteine. In contrast, non-tumorigenic cells proliferate well in homocysteine media. Previous work from our laboratory has shown that cancer cells cultured in homocysteine medium increase metabolic flux towards the transsulfuration pathway, away from S-adenosylmethionine (SAM) synthesis resulting in overall reduced methylation potential. We have shown that methionine sensing occurs independently of the mTOR pathway, which is known to link amino acid abundance and cell growth. Instead, our results suggest that Protein Phosphatase 2A (PP2A) methylation is sensitive to changes in the SAM/SAH ratio. Reduced PP2A methylation correlates with reduced cell proliferation in homocysteine medium. Furthermore, overexpression of the PP2A demethylase Pme1 forcibly reduces PP2A methylation and induces methionine dependence in cells that normally proliferate in homocysteine medium. These findings suggest a model that links methionine metabolism to cell cycle progression via regulation of PP2A methylation. Here we use quantitative proteomics to define changes in B-subunit binding to PP2A during methionine starvation to investigate the molecular mechanism of this methionine dependence seen in cancer. Citation Format: Anna Andronicos, Da-Wei Lin, Yi-Chen Su, Mari Ishak Gabra, Mei Kong, Peter Kaiser. Role of PP2A methylation on methionine dependence of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6045.
Abstract 6040: The CHST11-CP-iron axis contributes to NSCLC stemness
Authors: Li-Jie Li, Wei-Min Chang, Michael Hsiao
Journal: Cancer Research (2023)

Abstract The emerging advances in cancer therapies have changed the landscape for the treatment, but there are limited treatments options for advanced non-small-cell lung cancer (NSCLC). Cancer stem cell-induced chemoresistance and tumor metastasis accounts for treatment failure and recurrence in NSCLC. Additionally, the up-regulated glycosaminoglycan-chondroitin sulfate (CS) biosynthesis pathway contributes to the mesenchymal state of lung cancer and related to unfavorable prognosis. Previously, we found carbohydrate sulfotransferase 11 (CHST11), a key CS biosynthetic enzyme, was associated with tumor progression and metastasis in NSCLC as well as lung fibrosis. Furthermore, ceruloplasmin (CP) acted as a downstream effector of CHST11 through interferon-γ signaling pathway stimulation and increased NSCLC metastatic features. However, the linkage between metabolic dysregulation and NSCLC stemness remains unclear. Here, we found not only overexpression of CHST11 but also CS-A treatment, the metabolite of CHST11, promoted NSCLC tumor sphere formation, the expression of cancer stemness markers, and transcriptional activities of stemness-related pathways. Iron was a necessary ion in upregulating cancer stemness properties such as tumor-initiation, metastasis and chemoresistance. We found both CHST11 and iron enhanced NSCLC tumorigenesis. Moreover, iron chelation disrupted CHST11-CP axis induced-stemness. The combination of iron chelator with chemotherapies showed the synergistic effect on antitumor as well as anti-cancer stemness and further promoted apoptosis. Our findings implicate that the CHST11-CP-iron axis facilitates tumor progression and cancer stemness in NSCLC. A regimen that combines an iron chelator and chemotherapies targeting cancer stem cells will benefit for not only preventing NSCLC tumorigenesis but cancer recurrence. Citation Format: Li-Jie Li, Wei-Min Chang, Michael Hsiao. The CHST11-CP-iron axis contributes to NSCLC stemness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6040.
Abstract 821: Targeting metastatic prostate cancer using planetary ball-milled (PBM) nanoparticles
Authors: Santosh K. Singh, James W. Lillard, Rajesh Singh
Journal: Cancer Research (2023)

Abstract Men are most likely to develop prostate cancer (PCa), which has a high morbidity and fatality rate. Chemotherapy, the most recommended therapeutic strategy to combat PCa, has shown adverse effects on patients and develops drug-resistant PCa resulting in overall restricted survival of the patients. Many studies have demonstrated that natural compound-mediated therapy can be an effective option for treating PCa. Among the natural compounds, Thymoquinone (TQ), a derivative of Nigella sativa, has shown anti-proliferative, antioxidant, and anti-cancer effects. However, issues remain regarding its bioavailability, safety, and effective delivery system to cancer cells in vivo. In this study, we developed TQ nanoparticles (NPs) alone or in combination with DTX-encapsulated planetary ball-milled nanoparticles (PBM-NPs), formulated with starch (natural polysaccharides) inner core and biodegradable co-polymers poly (ε-caprolactone)/poly (ethylene glycol), functionalized with a prostate-specific membrane antigen (PSMA) aptamer (A10) to target the metastatic niche in PCa metastasis pre-clinical (patient-derived xenograft (PDX) and intra-tibial metastatic (LNCaP, PC-3 cells were injected directly into the tibia of SCID mice.) models. To determine the minimum effective dose (MED), efficacy, and safety of PBM-NPs, mice were treated intravenously with dose levels of vehicle control (empty-PBM-NPs), DTX alone (5 mg/kg, weekly), TQ alone (10 mg/kg, weekly), and a combination of TQ and DTX (25-fold less than maximum tolerance dose) using PBM-NPs, respectively for five weeks. Blood serum chemistry for toxicity and immunohistochemistry were performed to characterize these metastatic models. Our results showed TQ+DTX PBM NPs suppressed p-EGFR, ERK1/2, ABCB1, and Caspase3-expression, which are regulated by the EGFR-dependent pathway. We detected OPG, RANKL, PTHrP, and ET-1 immunoreactivity in all xenografts in the bone. In conclusion, sustained-release of combination PBM NPs demonstrated more significant anti-tumor activity following their conjugation to a prostate cancer cell-specific ligand, the toxicity of the drug can be reduced, and effective concentrations of the drug can be maintained locally for prolonged periods and prevention of PCa bone metastasis. Citation Format: Santosh K. Singh, James W. Lillard, Rajesh Singh. Targeting metastatic prostate cancer using planetary ball-milled (PBM) nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 821.